Osteoporosis is a major public health problem, with over 50% of Caucasian women and nearly 20% of Caucasian men at risk for an osteoporotic fracture in their lifetime (NIH Osteoporosis and Related Bone Diseases - National Resource Center). While some of the predictors of peak bone mass (PBM) include genetic predisposition and environmental factors, such as physical activity and diet, peak bone mass is also influenced by rapid changes in reproductive hormone levels for both genders, especially estrogen and progesterone during the accelerated growth period. Despite its well-studied effects in the reproductive system, progesterone's effects on bone metabolism remain largely unknown. In our laboratory, mice whose nuclear progesterone receptors (PR) were rendered nonfunctional (PRKO) exhibited a rapid gain of bone mass (age 1-3 months) and greater peak bone mass but with a sex difference in magnitude of increase (3- fold higher PBM in females and +50% in males) in comparison to their wild type (WT) litter mates (Yao et al. 2009). Thus, the presence of progesterone nuclear receptors exerts inhibitory effects on bone formation during the period of rapid bone acquisition, and this inhibition is more profound in female mice. Based on our preliminary observations, we hypothesize that progesterone signaling inhibits bone formation during the rapid bone growth period such that peak bone mass is lower in females than in males. We further hypothesize that inhibition of progesterone signaling in osteoblasts during the period of rapid bone acquisition period accelerates achievement of peak bone mass, especially for females. To test our hypotheses, we propose the following specific aims: Specific Aim 1: To investigate the direct effects of PR deletion on osteoblast and bone formation and compare these effects in female and male mice. Specific Aim 2: To determine if the inhibition of PR in vivo will lead to an uncoupling of bone turnover, we will monitor bone architecture and bone turnover changes following these interventions to determine how these interventions affect peak bone mass acquisition and if the responses would be differ between the sexes. RELEVANCE (See instructions): Osteoporosis is a major public health problem that currently affects 44 million Americans. Progesterone is known for its effects on the reproductive system, but its physiological roles in skeletal metabolism remains unclear. This study aims to clarify differences in peak bone mass acquisition between sexes with the overall goal of explaining sex differences in musculoskeletal diseases across the lifespan.